Purpose: To determine the role of UCH-L1 in regulating ERα expression, and to evaluate whether therapeutic targeting of UCH-L1 can enhance the efficacy of anti-estrogen therapy against breast cancer with loss or reduction of ERα.

Methods: Expressions of UCH-L1 and ERα were examined in breast cancer cells and patient specimens. The associations between UCH-L1 and ERα, therapeutic response and prognosis in breast cancer patients were analyzed using multiple databases. The molecular pathways by which UCH-L1 regulates ERα were analyzed using immunoblotting, qRT-PCR, immunoprecipitation, ubiquitination, luciferase and ChIP assays. The effects of UCH-L1 inhibition on the efficacy of tamoxifen in ERα (-) breast cancer cells were tested both in vivo and in vitro.

Results: UCH-L1 expression was conversely correlated with ERα status in breast cancer, and the negative regulatory effect of UCH-L1 on ERα was mediated by the deubiquitinase-mediated stability of EGFR, which suppresses ERα transcription. High expression of UCH-L1 was associated with poor therapeutic response and prognosis in patients with breast cancer. Up-regulation of ERα caused by UCH-L1 inhibition could significantly enhance the efficacy of tamoxifen and fulvestrant in ERα (-) breast cancer both in vivo and in vitro.

Conclusions: Our results reveal an important role of UCH-L1 in modulating ERα status and demonstrate the involvement of UCH-L1-EGFR signaling pathway, suggesting that UCH-L1 may serve as a novel adjuvant target for treatment of hormone therapy-insensitive breast cancers. Targeting UCH-L1 to sensitize ER negative breast cancer to anti-estrogen therapy might represent a new therapeutic strategy that warrants further exploration.

目的：确定 UCH-L1 在调节 ERα 表达中的作用，并评估 UCH-L1 的治疗靶向是否可以增强抗雌激素治疗对 ERα 丢失或减少的乳腺癌的疗效。

方法：检测乳腺癌细胞和患者标本中 UCH-L1 和 ERα 的表达。使用多个数据库分析了 UCH-L1 和 ERα 之间的关联、乳腺癌患者的治疗反应和预后。使用免疫印迹、qRT-PCR、免疫沉淀、泛素化、荧光素酶和 ChIP 检测分析了 UCH-L1 调节 ERα 的分子途径。在体内和体外测试了 UCH-L1 抑制对他莫昔芬在 ERα (-) 乳腺癌细胞中的功效的影响。

结果：UCH-L1表达与乳腺癌ERα状态呈负相关，UCH-L1对ERα的负调控作用是由去泛素化酶介导的EGFR稳定性介导的，抑制ERα转录。UCH-L1 的高表达与乳腺癌患者的不良治疗反应和预后相关。UCH-L1 抑制引起的 ERα 上调可以显着增强他莫昔芬和氟维司群在体内和体外治疗 ERα (-) 乳腺癌的疗效。

结论：我们的结果揭示了 UCH-L1 在调节 ERα 状态中的重要作用，并证明了 UCH-L1-EGFR 信号通路的参与，表明 UCH-L1 可作为治疗激素疗法不敏感乳腺癌的新辅助靶点. 靶向 UCH-L1 使 ER 阴性乳腺癌对抗雌激素治疗敏感可能代表一种新的治疗策略，值得进一步探索。